Background. Preoperative blood transfusion has had a significant historic impact on graft outcome in clinical kidney transplantation, and the effect has been widely replicated in many experimental transplant models. Although the mechanisms underlying the blood-transfusion effect are poorly understood, one possibility is that preexposure to alloantigen results in the induction of regulatory cells with the capacity to control the effector arm of the immune response. Methods. Recent studies in autoimmune models have shown that T cells with regulatory function can be isolated from unmanipulated animals on the basis of CD25 expression, and we have recently shown that pretreatment of recipient mice with donor alloantigen combined with anti-CD4 antibody therapy generates CD25 + CD4 + T cells that can prevent graft rejection. We therefore used this sensitive adoptive transfer mouse model to ask whether blood transfusion in the absence of any other treatment can also lead to the generation of alloreactive CD25 + CD4 + regulatory T cells. Results. Although a single donor-specific transfusion (DST) fails to induce dominant regulation, we demonstrate that pretreatment with multiple DSTs generates CD25 + CD4 + T cells that are as effective as those that result from blood transfusion under anti-CD4 antibody cover. More importantly, our results show that these cells also develop following multiple transfusions of unrelated (random) blood. Conclusion. These results provide a basis for understanding the blood-transfusion effect in transplantation and, by providing a link between naturally occurring regulatory cells and those induced by alloantigen, may shed new light on the fundamental basis of the effect itself.

Pretransplant blood transfusion without additional immunotherapy generates CD25+CD4+ regulatory T cells: a potential explanation for the blood-transfusion effect.

Background. Allograft survival can be prolonged by the administration of alloantigen(s) before transplantation. Blood transfusion is the commonest form of alloantigen pretreatment currently used in clinical practice. However, for recipients of organs from cadaver donors, it is not possible to predict the identity of the organ donor in advance. Therefore, it is highly unlikely that all the alloantigens expressed by a cadaver organ donor will be represented in the alloantigen pretreatment inoculum. We have previously shown that it is not necessary to expose the recipient to the full complement of donor alloantigens to induce long-term survival of a subsequent cardiac allograft. Here, we investigated the in vivo mechanism responsible for this phenomena. Methods. Unresponsiveness to the mouse MHC class I molecule K b was induced in CBA.Ca (H2 k ) recipients by administration of bone marrow cells from transgenic CBA mice, CBK (H2 k + K b ) before transplantation of fully allogeneic and F 1 vascularized cardiac allografts. Results. Pretreatment with CBK bone marrow cells resulted in the long-term survival of all cardiac allografts expressing H2-K b . For example, C57BL/10 (H2 b ) and (CBKxBALB/c) F 1 (H2 k,d + K b ) cardiac allografts were accepted by recipients treated with CBK bone marrow cells before transplantation. In contrast, allografts that did not express K b , such as BALB/c (H2 d ) ) or (CBAxBALB/c) F 1 (H2 k,d ), were rejected acutely, with a median survival time (MST) of 7 and 6 days, respectively, in recipients treated with CBK bone marrow cells. Furthermore, when recipients pretreated with CBK bone marrow cells were grafted with a BALB/c heart and a CBK heart simultaneously, the BALB/c hearts were rejected (MST=10 days), whereas the CBK hearts were accepted. By contrast, in the maintenance phase (i.e., after transplantation), recipients with long-term surviving (CBKxBALB/c) F 1 hearts (>100 days) were found to accept BALB/c hearts indefinitely, whereas fourth-party B10.S (H2 s ) grafts were rejected (MST=7.5 days). This indicated that the allografts bearing K b could tolerize recipients to other alloantigens expressed by the transplanted heart. Conclusions. These data provide clear evidence for linked epitope suppression in the induction of operational tolerance in vivo.

Pretransplant administration of a single donor class I major histocompatibility complex molecule is sufficient for the indefinite survival of fully allogeneic cardiac allografts: evidence for linked epitope suppression.

Blood transfusions appear to exert a suppressive effect on many aspects of the immune system In transplantation, this has been used to advantage; in other areas, the consequences can be deleterious It is likely that various components of the immune system are affected by different mechanisms and possibly by different components of transfused blood Before rational strategies can be evolved for minimizing the deleterious effects of blood transfusions, it is essential that these mechanisms be clearly defined Studies must take into account any influence the underlying disease state might have on the immune system In the absence of any satisfactory substitute, blood transfusion remains an essential therapeutic modality in the management of surgical patients With current evidence, however, it seems reasonable to avoid the administration of small-volume transfusions whenever possible and encourage the use of autodonated blood for elective surgery

Immunologic effects of blood transfusion upon renal transplantation, tumor operations, and bacterial infections.

This review summarizes three aspects of current research on the immunomodulatory effect of allogeneic transfusion. Representatives of three laboratories-each of which is actively engaged in research on transfusion-induced immunomodulation-summarize their current investigative approach. First, current animal models of transfusion-induced immunomodulation are presented and research on the tumor growth-promoting effect of allogeneic transfusion is described. Second, mechanisms underlying an immunomodulatory effect of transfusion are summarized and experiments on the induction of transplant tolerance by selective introduction of donor-type MHC antigens is presented. Third, the potential clinical impact of increased infection and tumor recurrence resulting from transfusion-induced immunomodulation is assessed. The potential role of donor-derived hematopoietic stem cells is presented as an area of future investigation in the area of transfusion-induced immunomodulation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1423-0410.1996.tb01324.x

Current Research on the Immunomodulatory Effect of Allogeneic Blood Transfusion

Both self and non-inherited maternal HLA antigens influence the immune response

PATIENTS in terminal renal failure who are awaiting renal transplantation are generally maintained on frequent bremodialysis. This period of maintenance may last for several months, during which time the patient may receive a number of whole blood transfusions, depending on the type of machine used for dialysis. This ranges from no transfusions to as many as 100 transfusions in the months immediately before transplantation. As it is known that leukocytes carry transplantation antigens (Medawar, 1946; Friedman et alii, 1961; Rapaport et alii, 1964), it might be expected that these frequent transfusions of whole blood (with leukocytes) would lead commonly to sensitization of potential recipients against a subsequent renal allograft. In fact, because of this theoretical risk of sensitization, many transplantation units use only leukocyte-free blood for transfusions. If this risk is real, it should be possible to demonstrate that renal allografts have a stormier early course, as judged by rejection crises, when the recipient has received a large number of transfusions before grafting. As just the opposite is suggested to be the case by two other units (Dossetor et alii, 1967; Michielsen, 1966), we have examined our own experience in this regard. We, too, are not able to show evidence of sensitization of recipients of renal allografts by whole-blood transfusions, thus providing the paradox alluded to in the title. The implications of the results to be described will be discussed at some length.

John Stocker

Papers

Leukocyte antigens in renal transplantation. 1. The paradox of blood transfusions in renal transplantation.